RGS PROTEIN FUNCTION AND REGULATION

RGS 蛋白的功能和调节

基本信息

批准号：
8282725
负责人：
Kendall J Blumer
金额：
$ 55.36万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8282725
关键词：
Acetylcholine Address Affect American Animals Antihypertensive Agents Arteries Attenuated Biochemical Biological Biological Assay Blood Pressure Blood Vessels Bradykinin Bradykinin Receptor Brain Stem Cardiovascular system Cell membrane Cells Clinical Coupled Cyclic GMP-Dependent Protein Kinases Data Defect Development Diabetes Mellitus Distal Endothelial Cells Endothelium Exhibits G-Protein Signaling Pathway GTP-Binding Proteins GTPase-Activating Proteins Gene Expression Genes Genetic Genetic Polymorphism Goals Human Hypertension Image In Vitro Investigation Kidney Kidney Failure Knock-in Mouse Knock-out Knockout Mice Life Link Liquid substance Luciferases Maintenance Mediating Mesentery Missense Mutation Modeling Mus Muscarinics Mutation Nephrons Nitric Oxide Organ Patients Phospholipase C Physiological Production Protein Subunits Publishing Quantitative Trait Loci RGS Proteins Reflex control Regulation Relative (related person)Relaxation Reporter Resistance Rho-associated kinase Risk Factors Role Severities Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Stroke Structure Syndrome System Testing Therapeutic Tissues Transgenic Mice Vascular Endothelium Vascular Endothelium-Dependent Relaxation Vascular Smooth Muscle Vasoconstrictor Agents Vasodilator Agents Vasopressin Receptor Vasopressins antidiuresis base blood pressure regulation cardiovascular disorder risk cell type human RGS2 protein human population study imaging modality improved in vivo innovation mRNA Expression mortality mouse model multicatalytic endopeptidase complex novel patient population protein function public health relevance receptor recombinase research study response ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to identify functions of RGS proteins and the mechanisms that regulate them. The focus of the present application is RGS2, which has been linked genetically in mice and humans to hypertension. The central hypothesis is that RGS2 regulates blood pressure by carrying out discrete functions in vascular smooth muscle, vascular endothelium, and kidney. This project focuses on the ability of RGS2 to regulate vascular contraction and relaxation by functioning in vascular smooth muscle, endothelium and to regulate fluid transport in renal nephron. It uses cell type- specific RGS2 knockout mice in conjunction with biochemical, cell biological, physiological and imaging methods to address the following Specific Aims: 1) determine how RGS2 degradation is regulated in vascular smooth muscle; 2) determine the relative contributions of RGS2 in vascular smooth muscle, endothelium and nephron in blood pressure control; 3) determine how RGS2 promotes endothelium-dependent vascular relaxation; and 4) determine whether RGS2 regulates the ability of vasoconstrictors to regulate RhoA signaling ex vivo and in vivo. Accordingly, this project advances understanding of blood pressure control mechanisms and their dysregulation in hypertension, which may contribute to the identification of new hypertension therapies. PUBLIC HEALTH RELEVANCE: Hypertension affects 50 million Americans, making this condition a leading mortality risk factor due to its association with greatly increased risk of cardiovascular disease, renal failure, diabetes and stroke. Hypertension causes enormous clinical and societal burden because ~70% of the patient population is poorly treated by currently available therapeutics. Improved treatment is likely to occur when therapeutics can be tailored to a patient's genetics. This project advances this goal by determining how a newly identified hypertension-linked gene---RGS2-regulates blood pressure.

描述（由申请人提供）：该项目的长期目标是确定 RGS 蛋白的功能及其调节机制。本申请的重点是 RGS2，它在小鼠和人类中与高血压存在遗传关联。核心假设是 RGS2 通过在血管平滑肌、血管内皮和肾脏中执行离散功能来调节血压。该项目重点研究 RGS2 通过在血管平滑肌、内皮细胞中发挥作用来调节血管收缩和舒张的能力，以及调节肾单位液体运输的能力。它使用细胞类型特异性 RGS2 敲除小鼠，结合生化、细胞生物学、生理学和成像方法来解决以下具体目标：1）确定血管平滑肌中如何调节 RGS2 降解； 2)确定RGS2在血管平滑肌、内皮和肾单位中在血压控制中的相对贡献； 3）确定RGS2如何促进内皮依赖性血管舒张； 4)确定RGS2是否调节血管收缩剂在离体和体内调节RhoA信号传导的能力。因此，该项目增进了对血压控制机制及其在高血压中的失调的理解，这可能有助于确定新的高血压疗法。公共卫生相关性：高血压影响着 5000 万美国人，由于它与心血管疾病、肾衰竭、糖尿病和中风的风险大大增加有关，因此成为主要的死亡风险因素。高血压造成巨大的临床和社会负担，因为目前可用的治疗方法对约 70% 的患者群体治疗效果不佳。当治疗方法可以根据患者的基因进行定制时，治疗可能会得到改善。该项目通过确定新发现的高血压相关基因 RGS2 如何调节血压来推进这一目标。